Abstract
Colorectal cancer (CRC, also known as colon cancer, rectal cancer, or bowel cancer) is the second leading cause of cancer mortality in the Western world. MicroRNAs (miRNAs) are a class of small (18–25 nucleotides long) noncoding RNAs with important posttranscriptional regulatory functions. miRNAs play important roles in various physiological and pathological processes including carcinogenesis in various solid cancers including CRC. In order to investigate the roles that miRNAs played in CRC, the expression of human miRNAs (in 20 normal adjacent tissue samples and 20 colon cancer samples) was examined in this study. miR-455, miR-484, and miR-101 were significantly downregulated in colon cancer samples. And overexpression of miR-455 significantly inhibited the proliferation and the invasion of SW480, but had no effect on apoptosis. PCR and Western blot showed that overexpression of miR-455 decreased protein expression of RAF proto-oncogene serine/threonine-protein kinase (RAF1) but had no effect on mRNA level. Luciferase assay indicated that miR-455 regulated RAF1 expression directly. Moreover, overexpression of RAF1 partially reversed the inhibitory effect of miR-455 on the growth and the invasion of SW480. The data indicated that miR-455 regulates the proliferation and invasion of colorectal cancer cells, at least in part, by downregulating RAF1, a direct target of miR-455. Collectively, our study demonstrated that miR-455-RAF1 may represent a new potential therapeutic target for colorectal carcinoma treatment.
Similar content being viewed by others
References
Greenlee RT, Hill-Harmon MB, Murray T, Thun M. Cancer statistics, 2001. CA Cancer J Clin. 2001;51:15–36.
Parkin DM. Global cancer statistics in the year 2000. Lancet Oncol. 2001;2:533–43.
Parkin DM, Bray F, Ferlay J, Pisani P. Global cancer statistics, 2002. CA Cancer J Clin. 2005;55:74–108.
Schepeler T, Reinert JT, Ostenfeld MS, Christensen LL, Silahtaroglu AN, Dyrskjot L, et al. Diagnostic and prognostic microRNAs in stage ii colon cancer. Cancer Res. 2008;68:6416–24.
Jemal A, Siegel R, Xu J, Ward E. Cancer statistics, 2010. CA Cancer J Clin. 2010;60:277–300.
Ferlay J, Shin HR, Bray F, Forman D, Mathers C, Parkin DM. Estimates of worldwide burden of cancer in 2008: Globocan 2008. Int J Cancer J Int du Cancer. 2010;127:2893–917.
Reid JF, Sokolova V, Zoni E, Lampis A, Pizzamiglio S, Bertan C, et al. Mirna profiling in colorectal cancer highlights mir-1 involvement in met-dependent proliferation. Mol Cancer Res MCR. 2012;10:504–15.
Jemal A, Center MM, DeSantis C, Ward EM. Global patterns of cancer incidence and mortality rates and trends cancer epidemiology, biomarkers & prevention. Publ Am Assoc Cancer Res Cosponsored Am Soc Prev Oncol. 2010;19:1893–907.
Bartel DP. MicroRNAs: genomics, biogenesis, mechanism, and function. Cell. 2004;116:281–97.
Nakasa T, Miyaki S, Okubo A, Hashimoto M, Nishida K, Ochi M, et al. Expression of microRNA-146 in rheumatoid arthritis synovial tissue. Arthritis Rheum. 2008;58:1284–92.
Schetter AJ, Okayama H, Harris CC. The role of microRNAs in colorectal cancer. Cancer J. 2012;18:244–52.
Michael MZ SMOC, van Holst Pellekaan NG, Young GP, James RJ. Reduced accumulation of specific microRNAs in colorectal neoplasia. Mol Cancer Res: MCR. 2003;1:882–91.
Luo X, Burwinkel B, Tao S, Brenner H. MicroRNA signatures: novel biomarker for colorectal cancer. Cancer Epidemiol Biomarkers Prev : Publ Am Assoc Cancer Res Cosponsored Am Soc of Prev Oncol. 2011;20:1272–86.
Cummins JM, He Y, Leary RJ, Pagliarini R, Diaz Jr LA, Sjoblom T, et al. The colorectal microRNAome. Proc Natl Acad Sci U S A. 2006;103:3687–92.
Schetter AJ, Leung SY, Sohn JJ, Zanetti KA, Bowman ED, Yanaihara N, et al. MicroRNA expression profiles associated with prognosis and therapeutic outcome in colon adenocarcinoma. JAMA : J Am Med Assoc. 2008;299:425–36.
Volinia S, Calin GA, Liu CG, Ambs S, Cimmino A, Petrocca F, et al. A microRNA expression signature of human solid tumors defines cancer gene targets. Proc Natl Acad Sci U S A. 2006;103:2257–61.
Mattick JS, Makunin IV: Small regulatory RNAs in mammals. Human molecular genetics 2005;14 Spec No 1:R121-132.
Nam EJ, Yoon H, Kim SW, Kim H, Kim YT, Kim JH, et al. MicroRNA expression profiles in serous ovarian carcinoma. Clin Cancer Res: Off J Am Assoc Cancer Res. 2008;14:2690–5.
Nagadia R, Pandit P, Coman WB, Cooper-White J, Punyadeera C. MiRNAs in head and neck cancer revisited. Cell Oncol. 2013;36:1–7.
Calin GA, Croce CM. MicroRNA signatures in human cancers. Nat Rev Cancer. 2006;6:857–66.
Iorio MV, Croce CM. MicroRNAs in cancer: Small molecules with a huge impact. J Clin Oncol : Off J Am Soc Clin Oncol. 2009;27:5848–56.
Wang YW, Shi DB, Chen X, Gao C, Gao P. Clinicopathological significance of microRNA-214 in gastric cancer and its effect on cell biological behaviour. PLoS ONE. 2014;9:e91307.
Li Y, Li W, Zhang JG, Li HY, Li YM: Downregulation of tumor suppressor menin by mir-421 promotes proliferation and migration of neuroblastoma. Tumour biology : the journal of the International Society for Oncodevelopmental Biology and Medicine 2014
Ma Y, She XG, Ming YZ, Wan QQ: Mir-24 promotes the proliferation and invasion of hcc cells by targeting sox7. Tumour biology : the journal of the International Society for Oncodevelopmental Biology and Medicine 2014
Wu JH, Yao YL, Gu T, Wang ZY, Pu XY, Sun WW, et al. Mir-421 regulates apoptosis of bgc-823 gastric cancer cells by targeting caspase-3. Asian Pac J Cancer Prev : APJCP. 2014;15:5463–8.
Ujifuku K, Mitsutake N, Takakura S, Matsuse M, Saenko V, Suzuki K, et al. Mir-195, mir-455-3p and mir-10a (*) are implicated in acquired temozolomide resistance in glioblastoma multiforme cells. Cancer Lett. 2010;296:241–8.
Hu Z, Shen WJ, Kraemer FB, Azhar S. MicroRNAs 125a and 455 repress lipoprotein-supported steroidogenesis by targeting scavenger receptor class b type i in steroidogenic cells. Mol Cell Biol. 2012;32:5035–45.
Li X, Zhang G, Luo F, Ruan J, Huang D, Feng D, et al. Identification of aberrantly expressed miRNAs in rectal cancer. Oncol Rep. 2012;28:77–84.
Swingler TE, Wheeler G, Carmont V, Elliott HR, Barter MJ, Abu-Elmagd M, et al. The expression and function of microRNAs in chondrogenesis and osteoarthritis. Arthritis Rheum. 2012;64:1909–19.
Kyriakis JM, App H, Zhang XF, Banerjee P, Brautigan DL, Rapp UR, et al. Raf-1 activates map kinase-kinase. Nature. 1992;358:417–21.
Brennan DF, Dar AC, Hertz NT, Chao WC, Burlingame AL, Shokat KM, et al. A raf-induced allosteric transition of ksr stimulates phosphorylation of mek. Nature. 2011;472:366–9.
Li P, Wood K, Mamon H, Haser W, Roberts T. Raf-1: a kinase currently without a cause but not lacking in effects. Cell. 1991;64:479–82.
Xu ZH, Hang JB, Hu JA, Gao BL. Raf1-mek1-erk/akt axis may confer nsclc cell lines resistance to erlotinib. Int J Clin Exp Pathol. 2013;6:1493–504.
Chen L, Wang Q, Wang GD, Wang HS, Huang Y, Liu XM, et al. Mir-16 inhibits cell proliferation by targeting igf1r and the raf1-mek1/2-erk1/2 pathway in osteosarcoma. FEBS Lett. 2013;587:1366–72.
Albers C, Illert AL, Miething C, Leischner H, Thiede M, Peschel C, et al. An RNAi-based system for loss-of-function analysis identifies raf1 as a crucial mediator of bcr-abl-driven leukemogenesis. Blood. 2011;118:2200–10.
Kobayashi T, Aoki Y, Niihori T, Cave H, Verloes A, Okamoto N, et al. Molecular and clinical analysis of raf1 in noonan syndrome and related disorders: Dephosphorylation of serine 259 as the essential mechanism for mutant activation. Hum Mutat. 2010;31:284–94.
Acknowledgments
We thank Guangzhou Vipotion Biotechnology Co., Ltd. for the assistance in the vector construction of luciferase reporter assay.
Conflicts of interest
None
Author information
Authors and Affiliations
Corresponding author
Rights and permissions
About this article
Cite this article
Chai, J., Wang, S., Han, D. et al. MicroRNA-455 inhibits proliferation and invasion of colorectal cancer by targeting RAF proto-oncogene serine/threonine-protein kinase. Tumor Biol. 36, 1313–1321 (2015). https://doi.org/10.1007/s13277-014-2766-3
Received:
Accepted:
Published:
Issue Date:
DOI: https://doi.org/10.1007/s13277-014-2766-3